Retinal vascular diseases are a significant cause of blindness and visual impairment in the United States. Evidence from ophthalmic research suggests that tissue ischemia resulting from abnormal blood flow regulation and/or vasomotor function initiates or contributes to the pathogenesis of many ocular diseases. Indirect evidence indicates that autoregulation of blood flow occurs in the retinal vasculature;however, the underlying mechanisms that control retinal blood flow are not known. Our long-term objective is to improve the prevention and therapy of retinal diseases that are linked to impaired blood flow regulation in the retina. To reach this goal, a fundamental understanding of basic vasomotor behavior of retinal microvasculature is required. In this research proposal, an integrative plan was designed to characterize the local vasoregulation phenomena (i.e., myogenic and flow-dependent responses) in retinal arterioles and to study the interaction of these two responses at the single microvessel level in the retinal arteriolar network. The central hypothesis for the proposed research is that retinal arterioles actively respond, in a size-dependent manner, to stimulation by pressure (i.e., myogenic response) and flow (i.e., shear stress-induced vasodilation). The experiments will be performed in various branching orders of porcine retinal arterioles using isolated, cannulated vessel techniques to allow pressure and flow to be independently controlled. The role of endothelium and cellular pathways involved in vasoregulation will be determined. Professor Lih Kuo, the mentor for this K08 Award, previously established this novel isolated vessel technique for the study of coronary microvessels. Under his supervision, the candidate has obtained preliminary data that support the proposed hypothesis. Our expectation is that the results of these experiments will provide new insights into the local vasomotor regulatory mechanisms in the retinal microcirculation and ultimately allow for the development of new strategies to prevent and treat retinal diseases associated with microvascular dysfunction. In addition, this K08 Award will allow for protected time for the principal investigator to acquire the expertise and knowledge which are essential to his becoming an independent investigator in the area of ophthalmic vascular research.